The impact of vascular disease on morbidity and mortality is on the rise in the Western world. Atherosclerotic renal artery stenosis (ARAS), a common etiology of chronic kidney disease and renovascular hypertension, amplifies deterioration of renal function compared to RAS alone. Furthermore, by amplifying endothelial and epithelial cell injury and impairing vascular cellular repair mechanisms, atherosclerosis exacerbates irreversible damage in the stenotic kidney and blunts its ability to recover following revascularization. Adequate strategies to improve these grave outcomes are yet to be identified, but are in dire need. The working hypothesis underlying this proposal is that replenishment of autologous progenitor cells (APC) would restore renal cellular integrity and improve the function, structure, and recovery prospects of the ARAS kidney. This hypothesis will be tested in a novel pig model of unilateral ARAS that we have developed and characterized, using unique imaging approaches that we have refined to study single-kidney function and structure. APC will be isolated from peripheral blood, expanded in vitro, and then administered into the stenotic kidney in conjunction with renal angiography or percutaneous transluminal renal angioplasty (PTRA), to study longitudinally their effects on single-kidney hemodynamics, function, response to challenge, and recovery potential. The in vivo studies will be correlated with in vitro characterization of the in situ 3D architecture of the renal microcirculation, renal redox status, and morphology in APC-treated and -untreated kidneys. Our new preliminary data show that APC improved the function and structure of the ischemic kidney, demonstrating the feasibility of this approach to confer renal protection. These studies will pursue 2 specific aims. Specific Aim 1 will test the hypothesis that replenishment of APC would improve the basal function and structure of the ARAS kidney. Specific Aim 2 will test the hypothesis that enhancing cellular repair by intra-renal delivery of APC, immediately after PTRA and during the same procedure, would improve the response of the ARAS kidney to intervention and restore its recovery potential. The proposed studies may greatly advance our understanding of the pathogenesis of renal injury in ARAS, and establish a novel, clinically feasible therapeutic strategy. Furthermore, they may assist in development of strategies to identify predictors of renal viability and improve the success of treatment. Thus, these studies may contribute towards management of patients with atherosclerosis and renovascular disease. PUBLIC HEALTH RELEVANCE: There is a pressing need to define the mechanisms by which atherosclerotic renovascular disease damages the kidney, and develop strategies to protect it. The proposed studies may advance our understanding of the pathogenesis of renal injury, and will determine the ability of autologous progenitor cells (which can be isolated from the individual's peripheral blood, and help repair renal vascular and other cells) to improve renal outcomes in this disease. These studies are likely to shed important light into and have a substantial ramification for designing and directing diagnostic and therapeutic measures for management of patients with renovascular disease.